An asymmetry in the visual input across the eyes early in postnatal life causes amblyopia, the most common basis of uniocular blindness in humans. In amblyopia, the nonamblyopic eye dominates control of neuronal responses in the binocular visual cortex, while the ability of the amblyopic eye to stimulate cortical neurons may weaken to the point of functional blindness. Previous attempts to recover vision in adult amblyopes have had modest success, and we propose this is due in large part to the significant reduction of synaptic plasticity that occurs during cortical development. We propose that optimizing recovery from amblyopia in adulthood requires a two stage process: 1) the reactivation of synaptic plasticity in the adult amblyopic cortex (permissive step) and 2) focused visual experience to stimulate perceptual learning (instructive step). Two labs, including the Quinlan lab (Elizabeth Quinlan is a consultant in the proposed work) have recently shown that binocular visual deprivation (BD) in adulthood enhances synaptic plasticity in the adult cortex of experimental animals. In addition, BD prior to repetitive visual experience stimulates the recovery of spatial acuity in animal models of deep amblyopia. Here we propose to translate this finding to the treatment of amblyopia in humans. We propose to use 5 and 10 days of binocular visual deprivation (in other words, living in complete darkness) to promote synaptic plasticity in the amblyopic visual cortex, followed by 8 weeks of visual perceptual learning, to stimulate the recovery of visual function. While visual perceptual learning has been previously shown to enhance visual function in amblyopic adults, the gains are slow and modest. We predict that pre-treatment of the amblyopic visual system with binocular visual deprivation will enhance the magnitude and/or time course of learning-induced recovery from amblyopia. The team of investigators assembled to test this hypothesis is ideally composed for a comprehensive analysis of visual functions, including both psychophysics and physiology, to track changes in visual function at key milestones during the experiment. If successful, this work would transform therapy for adult amblyopia, and focus attention on the importance of enhancing synaptic plasticity as an adjunct to treatment and training in the central nervous system. Insights gained from this work could be extended to strabismus, eye movement control disorders, and the restoration of optimal neural function after damage from traumatic brain injury. The proposed experiments will also pioneer the use of binocular visual deprivation in human amblyopes, and develop standards for implementation, including participant care, monitoring, and safety during sequestration.